- Email: [email protected]
Losartan for cardiovascular disease in patients with and without diabetes in the LIFE study
CORRESPONDENCE
-blockers should be given to elderly hypertensive patients only with a background of a suitable, compatible, proven agent—eg, low-dose diuretics. John Malcolm Cruickshank Oxonian Cardiovascular Consultancy, Long Melford, Suffolk CO10 9DE, UK (e-mail: [email protected]) 1
2
3
4
5
Dahlöf B, Devereux RB, Kjeldsen SE, et al, for the LIFE study group. Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359: 995–1003. Lindholm LH, Ibsen H, Dahlöf B, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359: 1004–10. Cruickshank JM, Prichard BNC. Beta-blockers in clinical practice, 2nd edn. London: Churchill Livingstone, 1994: 66. Cruickshank JM, Higgins TJC, Pennert K, Thorpe JM, Zacharias FM, Zacharias FJ. The efficacy and tolerability of antihypertensive treatment based on atenolol in the prevention of stroke and the regression of left ventricular hypertrophy. J Hum Hypertens 1987; 1: 87–93. O’Rourke M. Arterial stiffening and vascular/ventricular interaction. J Hum Hypertens 1994; Sept 8 (suppl 1): S9–15.
Sir—I challenge the validity of Lars Lindholm and colleagues’ conclusion,1 since more Framingham risk scores, more smokers, more atrial fibrillation, worse baseline diabetes control (requiring increased medication), and more isolated systolic hypertension are listed in patients in the atenolol group than in the losartan group. Also, underuse of appropriate medicines among study patients exaggerates the benefit of losartan—eg, aspirin underuse is noted in only 47% of patients in each group, but patients with diabetes who have cardiac risk factors warrant aspirin prophylaxis.2 Non-use of aspirin may play a part in more cardiac events. Moreover, poor control of diabetes during the study may have triggered more events in the control group, since average glucose concentrations in the atenolol group were higher than those advised by the American Diabetes Association. Similarly, more losartan than atenolol patients were started on antidiabetic drugs during the study. Blood pressures were not adequately reduced in either group; the aim was only lower than 140/90 mm Hg, which was achieved by fewer than 40% of patients, although less than 130/80 is advised.3 Mean blood pressure was not lowered as much in the atenolol group as in the losartan group, which suggests
that a higher dose of atenolol might have been necessary to genuinely compare the efficacy of the two drugs. In summary, losartan does reduce cardiovascular complications, but any benefit over atenolol is exaggerated by undertreatment of cardiac risk factors and higher baseline morbidity in the atenolol group. Angiotensin-convertingenzyme inhibitors should remain the treatment of choice in such diabetic patients. Angiotensin-II-receptor inhibitors are reasonable alternatives. Jeffrey M Bloom Central Coast Primary Care, 1334 Marsh Street, San Luis Obispo, CA 93401, USA (e-mail: [email protected]) 1
2
3
4
Lindholm LH, Ibsen H, Dahlöf B, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359: 1004–10. Krein SL, Vijan S, Pogach LM, Hogan MM, Kerr EA. Aspirin use and counselling about aspirin among patients with diabetes. Diabetes Care 2002; 25: 965–70. Kaplan NM. Management of hypertension in patients with type 2 diabetes mellitus: guidelines based on current evidence. Ann Intern Med 2001; 135: 1079–83. Tsuyuki RT, Yusuf S, Rouleau JL, et al. Combination neurohormonal blockade with ACE inhibitors, angiotensin II antagonists and beta-blockers in patients with congestive heart failure: design of the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) pilot study. Can J Cardiol 1997; 13: 1166–74.
Sir—Although Björn Dahlöf and colleagues1 and Lars Lindholm and colleagues2 seem to report a welldesigned study, there is a troubling question. In the non-diabetic patients, the almost 15% reduction of the primary outcome driven solely by the 24% reduction of stroke, but in the diabetic patients, the 24% reduction in primary endpoint was driven mostly by reduction in cardiovascular and total mortality. Stroke rate reduction was not significant, but the stroke rates were at least 1·5–1·8 fold higher in diabetic patients than in non-diabetic patients.2 Moreover, in the RENAAL trial,3 the stroke rates for 1513 diabetic patients with renal failure, most of whom were hypertensive, did not differ. In most studies the power for endpoints such as stroke is higher than that for cardiovascular and total mortality. Thus lack of power in diabetic patients is not a likely explanation. One way to interpret these discrepancies may be that losartan is not beneficial for stroke reduction in diabetic patients at risk, and another that the finding, since in the non-diabetic hypertensive patients is a chance finding, since there
THE LANCET • Vol 359 • June 22, 2002 • www.thelancet.com
were no other benefits other than for stroke despite comparable bloodpressure reduction. Michael Bursztyn Hypertension unit, Department of Medicine, Hadassah University Hospital, Mount-Scopus, Jerusalem 91240, Israel (e-mail: [email protected]) 1 Dahlöf B, Devereux RB, Kjeldsen SE, et al, for the LIFE study group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359: 995–1003. 2 Lindholm LH, Ibsen H, Dahlöf B, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359: 1004–10. 3 Brenner BM, Cooper ME, de Zeeuw D, et al, for the RENAAL study investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345: 861–69.
Sir—Although the incidence of type 2 diabetes was not the primary outcome of Björn Dahlöf and colleagues’ study,1 the 2% absolute risk reduction of new-onset diabetes in the losartan group could effect future strategies to prevent diabetes. As the investigators state, this finding is in accordance with the results from previous trials with angiotensinconverting-enzyme (ACE) inhibitors, and adds further evidence to the potential beneficial effects inhibition of the renin-angiotensin system have on glucose tolerance. The important questions are whether ACE inhibitors and angiotensin-IIreceptor antagonists improve glucose tolerance, whether drugs used in the control groups have harmful effects on glucose metabolism, or both? Dahlöf and colleagues suggest a differential effect on insulin resistance, but Brunner and Gavras2 argue that atenolol-induced aggravation of glucose intolerance is most important. However, both insulin resistance and impaired early insulin release contribute to the development of type 2 diabetes. The effect of ACE inhibition on insulin sensitivity has been disputed, but findings of previous studies have shown that these drugs may actually increase the insulin secretory response as assessed with intravenous3 or oral4 glucose tolerance tests. The mechanism for the potential beneficial effects of ACE inhibitors on early insulin release is not fully understood. One plausible hypothesis is that ACE inhibition and angiotensin-II-receptor antagonism induce raised pancreatic islet blood flow, which is important to secure a sufficient
2201
For personal use. Only reproduce with permission from The Lancet Publishing Group.
-blockers should be given to elderly hypertensive patients only with a background of a suitable, compatible, proven agent—eg, low-dose diuretics. John Malcolm Cruickshank Oxonian Cardiovascular Consultancy, Long Melford, Suffolk CO10 9DE, UK (e-mail: [email protected]) 1
2
3
4
5
Dahlöf B, Devereux RB, Kjeldsen SE, et al, for the LIFE study group. Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359: 995–1003. Lindholm LH, Ibsen H, Dahlöf B, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359: 1004–10. Cruickshank JM, Prichard BNC. Beta-blockers in clinical practice, 2nd edn. London: Churchill Livingstone, 1994: 66. Cruickshank JM, Higgins TJC, Pennert K, Thorpe JM, Zacharias FM, Zacharias FJ. The efficacy and tolerability of antihypertensive treatment based on atenolol in the prevention of stroke and the regression of left ventricular hypertrophy. J Hum Hypertens 1987; 1: 87–93. O’Rourke M. Arterial stiffening and vascular/ventricular interaction. J Hum Hypertens 1994; Sept 8 (suppl 1): S9–15.
Sir—I challenge the validity of Lars Lindholm and colleagues’ conclusion,1 since more Framingham risk scores, more smokers, more atrial fibrillation, worse baseline diabetes control (requiring increased medication), and more isolated systolic hypertension are listed in patients in the atenolol group than in the losartan group. Also, underuse of appropriate medicines among study patients exaggerates the benefit of losartan—eg, aspirin underuse is noted in only 47% of patients in each group, but patients with diabetes who have cardiac risk factors warrant aspirin prophylaxis.2 Non-use of aspirin may play a part in more cardiac events. Moreover, poor control of diabetes during the study may have triggered more events in the control group, since average glucose concentrations in the atenolol group were higher than those advised by the American Diabetes Association. Similarly, more losartan than atenolol patients were started on antidiabetic drugs during the study. Blood pressures were not adequately reduced in either group; the aim was only lower than 140/90 mm Hg, which was achieved by fewer than 40% of patients, although less than 130/80 is advised.3 Mean blood pressure was not lowered as much in the atenolol group as in the losartan group, which suggests
that a higher dose of atenolol might have been necessary to genuinely compare the efficacy of the two drugs. In summary, losartan does reduce cardiovascular complications, but any benefit over atenolol is exaggerated by undertreatment of cardiac risk factors and higher baseline morbidity in the atenolol group. Angiotensin-convertingenzyme inhibitors should remain the treatment of choice in such diabetic patients. Angiotensin-II-receptor inhibitors are reasonable alternatives. Jeffrey M Bloom Central Coast Primary Care, 1334 Marsh Street, San Luis Obispo, CA 93401, USA (e-mail: [email protected]) 1
2
3
4
Lindholm LH, Ibsen H, Dahlöf B, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359: 1004–10. Krein SL, Vijan S, Pogach LM, Hogan MM, Kerr EA. Aspirin use and counselling about aspirin among patients with diabetes. Diabetes Care 2002; 25: 965–70. Kaplan NM. Management of hypertension in patients with type 2 diabetes mellitus: guidelines based on current evidence. Ann Intern Med 2001; 135: 1079–83. Tsuyuki RT, Yusuf S, Rouleau JL, et al. Combination neurohormonal blockade with ACE inhibitors, angiotensin II antagonists and beta-blockers in patients with congestive heart failure: design of the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) pilot study. Can J Cardiol 1997; 13: 1166–74.
Sir—Although Björn Dahlöf and colleagues1 and Lars Lindholm and colleagues2 seem to report a welldesigned study, there is a troubling question. In the non-diabetic patients, the almost 15% reduction of the primary outcome driven solely by the 24% reduction of stroke, but in the diabetic patients, the 24% reduction in primary endpoint was driven mostly by reduction in cardiovascular and total mortality. Stroke rate reduction was not significant, but the stroke rates were at least 1·5–1·8 fold higher in diabetic patients than in non-diabetic patients.2 Moreover, in the RENAAL trial,3 the stroke rates for 1513 diabetic patients with renal failure, most of whom were hypertensive, did not differ. In most studies the power for endpoints such as stroke is higher than that for cardiovascular and total mortality. Thus lack of power in diabetic patients is not a likely explanation. One way to interpret these discrepancies may be that losartan is not beneficial for stroke reduction in diabetic patients at risk, and another that the finding, since in the non-diabetic hypertensive patients is a chance finding, since there
THE LANCET • Vol 359 • June 22, 2002 • www.thelancet.com
were no other benefits other than for stroke despite comparable bloodpressure reduction. Michael Bursztyn Hypertension unit, Department of Medicine, Hadassah University Hospital, Mount-Scopus, Jerusalem 91240, Israel (e-mail: [email protected]) 1 Dahlöf B, Devereux RB, Kjeldsen SE, et al, for the LIFE study group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359: 995–1003. 2 Lindholm LH, Ibsen H, Dahlöf B, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359: 1004–10. 3 Brenner BM, Cooper ME, de Zeeuw D, et al, for the RENAAL study investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345: 861–69.
Sir—Although the incidence of type 2 diabetes was not the primary outcome of Björn Dahlöf and colleagues’ study,1 the 2% absolute risk reduction of new-onset diabetes in the losartan group could effect future strategies to prevent diabetes. As the investigators state, this finding is in accordance with the results from previous trials with angiotensinconverting-enzyme (ACE) inhibitors, and adds further evidence to the potential beneficial effects inhibition of the renin-angiotensin system have on glucose tolerance. The important questions are whether ACE inhibitors and angiotensin-IIreceptor antagonists improve glucose tolerance, whether drugs used in the control groups have harmful effects on glucose metabolism, or both? Dahlöf and colleagues suggest a differential effect on insulin resistance, but Brunner and Gavras2 argue that atenolol-induced aggravation of glucose intolerance is most important. However, both insulin resistance and impaired early insulin release contribute to the development of type 2 diabetes. The effect of ACE inhibition on insulin sensitivity has been disputed, but findings of previous studies have shown that these drugs may actually increase the insulin secretory response as assessed with intravenous3 or oral4 glucose tolerance tests. The mechanism for the potential beneficial effects of ACE inhibitors on early insulin release is not fully understood. One plausible hypothesis is that ACE inhibition and angiotensin-II-receptor antagonism induce raised pancreatic islet blood flow, which is important to secure a sufficient
2201
For personal use. Only reproduce with permission from The Lancet Publishing Group.